Disease relevance of GPR37

• Pael receptor, endoplasmic reticulum stress, and Parkinson's disease [1].
• Furthermore, we investigated the effects of 4-PBA on the accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R) pathologically relevant to the loss of dopaminergic neurons in autosomal recessive juvenile parkinsonism (AR-JP) [2].
• Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation [3].

High impact information on GPR37

• Parkin specifically ubiquitinates this receptor in the presence of ubiquitin-conjugating enzymes resident in the endoplasmic reticulum and promotes the degradation of insoluble Pael receptor, resulting in suppression of the cell death induced by Pael receptor overexpression [4].
• The insoluble Pael receptor leads to unfolded protein-induced cell death [4].
• Here we show in an organismal system that panneuronal expression of Parkin substrate Pael-R causes age-dependent selective degeneration of Drosophila dopaminergic (DA) neurons [5].
• Upregulation of Pael-R in the substantia nigra pars compacta of mice by retrograde infection induced endoplasmic reticulum (ER) stress leads to death of dopaminergic neurons [3].
• Pael-R is accumulated in Lewy bodies of Parkinson's disease [6].

Psychiatry related information on GPR37

• In the absence of Pael-R, overexpression of TRX in all neurons increased the level of locomotor activity in aged flies and extended the mean longevity by 15% [7].

Chemical compound and disease context of GPR37

• We examined the distribution of Pael-R, a newly identified substrate for Parkin, in Parkinson's disease (PD) and multiple system atrophy (MSA) [6].

Biological context of GPR37

• The GPR37 genomic sequence was mapped to chromosome 7q31, and it was isolated upon screening of a chromosome 7-specific genomic library [8].
• The GPR37 cDNA predicts a single open reading frame coding for a 613-amino-acid protein with seven hydrophobic transmembrane domains [8].
• Although the ligand for the putative GPR37 receptor has not been identified, its deduced amino acid sequence shows a high degree of homology (approximately 40% in the transmembrane regions) with most mammalian peptide-specific G-protein-coupled receptors and particularly with the human endothelin-B, bombesin-BB1, and bombesin-BB2 receptors [8].
• The GPR37 gene spans more than 25 kb and contains two exons and a single intron which interrupts the GPR37 cDNA within the sequence encoding the presumed third transmembrane domain [8].
• A cDNA sequence encoding a putative peptide-specific G-protein-coupled receptor (GPR37) was isolated from a set of human brain frontal lobe expressed sequence tags [8].

Anatomical context of GPR37

• Northern blot analysis with GPR37 probes revealed a main 3.8-kb mRNA and a less abundant 8-kb mRNA, both expressed in human brain tissues, particularly in corpus callosum, medulla, putamen, and caudate nucleus [8].
• Accumulation of the insoluble Pael-R subsequently led to endoplasmic reticulum (ER) stress-induced cell death [1].
• It is highly expressed by the dopaminergic neurons of the substantia nigra, strongly suggesting that accumulation of unfolded Pael-R may lead to selective death of dopaminergic neurons in AR-JP.Recently, we identified Hsp70 and its co-chaperone CHIP as novel parkin-binding partners [1].
• A product of the human gene adjacent to parkin is a component of Lewy bodies and suppresses Pael receptor-induced cell death [9].
• Inhibition of degradation of overexpressed Pael-R in cultured cells leads to the accumulation of misfolded Pael-R in the endoplasmic reticulum (ER) and induces ER stress, followed by cell death [10].

Associations of GPR37 with chemical compounds

• Parkin specifically ubiquitinates the unfolded Pael-R and promotes its degradation, resulting in suppression of cell death induced by the accumulation of unfolded Pael-R [1].
• Electrophysiological recordings in frog oocytes and in mammalian cell lines as well as Ca(2+) mobilisation assays revealed nanomolar affinities of HA to GPR37 [11].
• The predicted mouse GPR37 protein contains seven putative hydrophobic transmembrane domains, as well as a long (249 amino acid residues), arginine- and proline-rich amino-terminal extracellular domain, which is also a distinctive feature of the human GPR37 receptor [12].

Regulatory relationships of GPR37

• Specific binding of radiolabeled ET-1 and ET-3 to membrane preparations and to intact cells expressing recombinant protein of hET(B)R-LP/HA did not show any significant difference of binding properties between cells transfected with plasmid DNA, hET(B)R-LP/HA/pcDNA1/Amp, and cells untransfected, including both COS7 cells and HEK293 cells [13].

Other interactions of GPR37

• Moreover, insoluble Pael-R accumulates in the brains of AR-JP patients [1].
• Glup knockdown attenuated the formation of Pael-R inclusions, which resulted in the promotion of cell death with extensive vacuolization [9].
• We report here our effort of cloning and characterization of a novel human gene, which encodes a putative human endothelin receptor type B like protein (hET(B)R-LP), from a human hippocampus tissue cDNA library. hET(B)R-LP consists of 614 amino acids with seven putative transmembrane domains [13].

References